Anaplastic large cell lymphoma, ALK positive
Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
Synonyms and keywords: ALCL-ALK(+); ALK-positive ALCL; ALK positive ALCL; ALK positive anaplastic large cell lymphoma
Overview
The anaplastic large cell lymphoma (ALCL) ALK-positive (Anaplastic Llymphoma Kinase) is a peripheral T-cell lymphoma (non-Hodgkin lymphoma) characterized by the proliferation of CD30-positive T-cells which have an abundant cytoplasm, a pleomorphic nucleus (horseshoe-shaped nucleus), and an eosinophilic paranuclear region.[1] This type of ALK-positive lymphoma is associated with a translocation in the ALK gene [T(2;5)(p23;q35)] which expresses the ALK protein.[2]
Classification
Morphologic Classification[3]
Classical Variants
- Common pattern ALK positive anaplastic large cell lymphoma
Atypical Variants
- Small cell ALK positive anaplastic large cell lymphoma
- Lymphohistiocytic ALK positive anaplastic large cell lymphoma
- Giant cell ALK positive anaplastic large cell lymphoma
- Hodgkin's like ALK positive anaplastic large cell lymphoma
Rare Variants
- Sarcomatoid ALK positive anaplastic large cell lymphoma
Pathophysiology
The morphologic features of ALCL are variable. There are five morphological patterns:[2]
- "Common" pattern: This is the most common morphological variant (75%).[4] The cytoplasm may be either basophilic or eosinophilic and the cell might have many nuclei with dispersed or clumped chromatin. In large cells, nucleoli tend to be more prominent. Given that the lymphomatous cells grow in the lymph node's sinuses, this variant may resemble a metastatic tumor.
- Lymphohistiocytic pattern (10%): Histiocytes have an acidophilic cytoplasm and a perinuclear clear area, with an eccentric nuclei and condensed chromatin.[5] Lymphomatous cells cluster around the perivascular area as demonstrated by immunostaining with CD30 and ALK antibodies.[2]
- Hodgkin's like pattern (3.3%): The morphological characteristics of this pattern are similar to the nodular sclerosis variant of Hodgkin's lymphoma.[6] This pattern is predominately more common among female. There are two immunophenotype:[6]
- Small cell pattern (8.3%): Cells have nuclear irregularity and perivascular/intravascular distribution.[7] Occasionally, lymphomatous cells have a pale cytoplasm with a central nucleus, described as "fried egg cell".[2]
- Giant cell pattern (3.3%)
One single patient may present more than one morphologic pattern in the same or progressive biopsies[1].
Causes
ALK positive anaplastic large cell lymphoma is associated with a rearrangement in the anaplastic lymphoma kinase (ALK) gene. The most frequent gene translocation is T(2;5)(p23;q35).[8] This translocation leads to a chimeric protein between the nucleolar phosphoprotein (NPM) gene (5q35) and ALK gene (2p23), which has structural similarity to the insulin growth factor receptor.[9] Normal T-cells require IL-2 as a growth factor; T-cells of patients with ALK positive anaplastic large cell lymphoma have a constitutive activation of IL-2 receptor caused by the new NMP-ALK chimeric protein.[10]
Other gene mutations include:[11]
- T(1;2), encoding a tropomyosin3 (TPM3)/ALK fusion protein (10 to 20%)
- T(2;3), encoding a TRK fusion gene (TFP)/ALK fusion protein (2 to 5%
- Inv(2), encoding a ATIC (Pur H gene)/ALK fusion protein (2 to 5%)
- T(2;17), encoding a clathrin heavy (CLTC)/ALK fusion protein (2 to 5%)
- T(2;17), encoding a ALO17/ALK fusion protein (2 to 5 percent of cases)
- T(2;19), encoding a tropomyosin 4 (TPM4)/ALK fusion protein (<1%)
- T(2;22), encoding a non-muscle myosin (MYH9)/ALK fusion protein (<1%)
Differential Diagnosis
- ALCL ALK negative
- Primary cutaneous ALCL
- Diffuse large B-cell lymphoma, anaplastic type
- Diffuse large B-cell lymphoma, plasmablastic type
- Hodgkin lymphoma
Epidemiology and Demographics
ALK positive anaplastic large cell lymphoma affects primarily young (between 10 and 29 years), male patients[12] and accounts for 3% of all NHL, 40% of all large cell lymphomas[13] and 10%-20% of childhood lymphomas.ref>"ALK+ Lymphoma: Clinico-Pathological Findings and Outcome".</ref>
According to a study on 1,320 cases of peripheral T-cell lymphomas and NK cell lymphomas between 1990 and 2002 in 22 different centers, ALK-Positive ALCL is the fifth most common type of peripheral T cell lymphoma (6.6% of total patients).[14] In the United states, ALK-Positive ALCL is the most frequent type of peripheral T-cell lymphoma.
Natural History, Complications and Prognosis
Prognosis
The International Prognostic Iindex (IPI) is used to estimate the prognosis of patients.[15] The IPI takes into account 5 variables:
- Patient's age (>60 years)
- Elevated serum lactate dehydrogenase (LDH)
- Eastern Cooperative Oncology Group (ECOG) performance status
- Ann Arbor clinical stage III or IV
- Number of involved extra nodal sites > 1
If any of this criteria is met, one point is awarded for the IPI. The interpretation of the total score is as follows:
- 0 to 1: Low risk
- 2: Low-intermediate risk
- 3: High-intermediate risk
- 4 to 5: High risk
According to the International Peripheral T cell Lymphoma Project, the estimated 5-years survival for each of the IPI stages are as follows:[16]
- Low risk (IPI 0-1): 90%
- Low-intermediate risk (IPI 2): 68%
- High-intermediate risk (IPI 3): 23%
- High risk (IPI 4-5): 33%
Diagnosis
History and Symptoms
Most adult patients present with painless lymphadenopathy. Although retroperitoneal and peripheral lymphadenopathy is very common,[17] other possible locations for enlarged lymph nodes include the gastrointestinal tract, the breast,[18] the spleen,[19] the liver,[20] the bone,[20] the heart,[21] and the respiratory tract.[22]
Common symptoms include typical B symptoms: fever, weight loss, and night sweats.[23]
Laboratory Findings
- Anemia
- Thrombocytopenia
- Elevated lactate dehydrogenase (LDH)[24]
Treatment
CHOP-E Regimen
The CHOP-E regimen includes:
References
- ↑ 1.0 1.1 Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ; et al. (1998). "ALK-positive lymphoma: a single disease with a broad spectrum of morphology". Blood. 91 (6): 2076–84. PMID 9490693.
- ↑ 2.0 2.1 2.2 2.3 Swerdlow, Steven (2008). WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer. ISBN 9789283224310.
- ↑ "The anaplastic lymphoma kinase in the pathogenesis of cancer". Unknown parameter
|A188154738&docType=ignored (help) - ↑ Falini B, Bigerna B, Fizzotti M, Pulford K, Pileri SA, Delsol G; et al. (1998). "ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum". Am J Pathol. 153 (3): 875–86. doi:10.1016/S0002-9440(10)65629-5. PMC 1853018. PMID 9736036.
- ↑ "Frequent Expression ofthe NPM-ALK Chimeric Fusion Protein inAnaplastic Large-Cell Lymphoma, Lympho-Histiocytic Type" (PDF).
- ↑ 6.0 6.1 Vassallo J, Lamant L, Brugieres L, Gaillard F, Campo E, Brousset P; et al. (2006). "ALK-positive anaplastic large cell lymphoma mimicking nodular sclerosis Hodgkin's lymphoma: report of 10 cases". Am J Surg Pathol. 30 (2): 223–9. PMID 16434897.
- ↑ Kinney MC, Collins RD, Greer JP, Whitlock JA, Sioutos N, Kadin ME (1993). "A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma". Am J Surg Pathol. 17 (9): 859–68. PMID 8394652.
- ↑ Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL; et al. (1994). "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma". Science. 263 (5151): 1281–4. PMID 8122112.
- ↑ "Fusion of kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma". Unknown parameter
|A15341631&docType=ignored (help) - ↑ "Fusion of kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma". Unknown parameter
|A15341631&docType=ignored (help) - ↑ "The anaplastic lymphoma kinase in the pathogenesis of cancer".
- ↑ Stein H, Foss HD, Dürkop H, Marafioti T, Delsol G, Pulford K; et al. (2000). "CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features". Blood. 96 (12): 3681–95. PMID 11090048.
- ↑ "ALK+ Lymphoma: Clinico-Pathological Findings and Outcome".
- ↑ "International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes" (PDF).
- ↑ "International Prognostic Index for non-Hodgkin lymphoma".
- ↑ http://www.bloodjournal.org/content/111/12/5496.abstract?sso-checked=true. Text "title:ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project" ignored (help); Missing or empty
|title=(help) - ↑ Yu G, Gao Z, Huang X (2014). "ALK-positive anaplastic large cell lymphoma with an unusual alveolar growth pattern". Int J Clin Exp Pathol. 7 (12): 9086–9. PMC 4314028. PMID 25674293.
- ↑ Gidengil CA, Predmore Z, Mattke S, van Busum K, Kim B (2014). "Breast implant-associated anaplastic large cell lymphoma: a systematic review". Plast Reconstr Surg. doi:10.1097/PRS.0000000000001037. PMID 25490539.
- ↑ Hebeda KM, MacKenzie MA, van Krieken JH (2000). "A case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting with spontaneous splenic rupture: an extremely unusual presentation". Virchows Arch. 437 (4): 459–64. PMID 11097375.
- ↑ 20.0 20.1 Grewal JS, Smith LB, Winegarden JD, Krauss JC, Tworek JA, Schnitzer B (2007). "Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature". Ann Hematol. 86 (7): 499–508. doi:10.1007/s00277-007-0289-3. PMID 17396261.
- ↑ Lim ZY, Grace R, Salisbury JR, Creamer D, Jayaprakasam A, Ho AY; et al. (2005). "Cardiac presentation of ALK positive anaplastic large cell lymphoma". Eur J Haematol. 75 (6): 511–4. doi:10.1111/j.1600-0609.2005.00542.x. PMID 16313264.
- ↑ Tan DS, Eng PC, Lim ST, Thye LS, Tao M (2008). "Primary tracheal lymphoma causing respiratory failure". J Thorac Oncol. 3 (8): 929–30. doi:10.1097/JTO.0b013e318180271d. PMID 18670314.
- ↑ "T-cell lymphomas (Lymphoma Association)" (PDF).
- ↑ "ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project".